In the US of the 1.5 million fractures that occur annually, one-third of them occur in men. Osteoporosis and fracture-related disability are key health problems in older male veterans. Fractures also increase mortality. Men who fracture their hips have twice the mortality of women sustaining those same hip fractures. Several drugs are approved to treat osteoporosis in men [bisphosphonates, denosumab, and teriparatide (TPTD) or PTH(1-34)], but we have little insight as to how to use them most effectively. TPTD has great appeal for treating osteoporosis in men because it substantially improves bone mass, rebuilds the microarchitecture, improves bone strength, and reduces fractures. Little is known about the best ways to employ TPTD in the treatment of male osteoporosis. Should it be used only as monotherapy or does concurrent or sequential use with other agents lead to the greatest benefit? The proposed clinical trial is an effort to test a novel combination therapy for osteoporosis in men based on exciting preclinical findings in mice. It is known that TPTD achieves its anabolic effects by stimulating PTH receptors (PTH-Rs) in cells of the osteoblast (OB) lineage. Calcimimetics mimic the effects of high extracellular calcium concentrations ([Ca]e) by activating Ca- sensing receptors (CaSRs) expressed in many cell types including OBs and osteoclasts in bone. Work by us and other groups have found that CaSRs in OBs play an important role in controlling bone formation, OB differentiation, and mineralization. In preclinical models in the lab, we found that daily injections of TPTD given concurrently with an investigational calcimimetic agent (NPS-R568) in just 6 weeks markedly increased bone mass and improved both trabecular and cortical microarchitecture of bone as assessed by both micro- computed tomography and histomorphometry in adult male mice. Based on these results, we propose to test the hypothesis that concurrent activation of PTH-Rs and CaSRs (TPTD+calcimimetic cinacalcet) in men with low bone mineral density (BMD) produces greater anabolic responses than PTH-R activation alone (TPTD+placebo). To test this hypothesis, we propose a randomized, double-blinded, {{placebo-controlled clinical trial in 48 men with low bone mass}}. We plan two treatment arms. Aim 1 will determine the effects of 11 months treatment with TPTD+cinacalcet compared to TPTD+placebo on BMD and bone metabolism in men with low bone mass. We will assess responses in: (a) lumbar spine (LS) BMD (primary endpoint) and femoral neck (FN) BMD; and (b) levels of the bone formation marker serum N-terminal pro-peptide of type 1 collagen (P1NP). Hypothesis 1a proposes that LS and FN BMD responses are greater with TPTD+cinacalcet compared to TPTD+placebo. Hypothesis 1b proposes that serum P1NP increases are greater with TPTD+cinacalcet compared to TPTD+placebo. Aim 2 will determine the pharmacodynamic responses to TPTD+cinacalcet and to TPTD+placebo treatment in men with low bone mass. We will assess: (a) acute and chronic changes in the serum [Ca] and plasma intact PTH after drug administration in a pharmacodynamic study in a subset of 24 men (12/treatment arm); and (b) changes in urinary Ca excretion with both treatment regimens {in all 48 randomized men}. Hypothesis 2a proposes that serum [Ca] does not decrease to > 5% below the lower limits of the normal range in response to the administration of combined TPTD+cinacalcet. Hypothesis 2b proposes that urinary Ca excretion does not exceed 350 mg per 24 hours in men treated chronically with TPTD+cinacalcet. Completion of this study will provide critical evidence to support the efficacy of a novel combination therapy that is designed to target the concurrent activation of CaSRs and PTH-Rs in bone to achieve greater skeletal anabolic effects with the ultimate goal of improving skeletal health and reducing the disability, morbidity, and mortality of osteoporotic fractures in male veterans.